US4612376A - Substituted-3,4-dihydro-4-(2,4,6-trimethoxyphenylimino)-2(1H)-pyrimidones useful as cardiotonic, antihypertensive, cerebrovascular vasodilator and anti-platelet agent - Google Patents

Substituted-3,4-dihydro-4-(2,4,6-trimethoxyphenylimino)-2(1H)-pyrimidones useful as cardiotonic, antihypertensive, cerebrovascular vasodilator and anti-platelet agent Download PDF

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US4612376A
US4612376A US06/588,902 US58890284A US4612376A US 4612376 A US4612376 A US 4612376A US 58890284 A US58890284 A US 58890284A US 4612376 A US4612376 A US 4612376A
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dimethoxyphenyl
compound
dihydro
pyrimidinone
methyl
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Takao Takaya
Masayoshi Murata
Kiyotaka Ito
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Priority claimed from GB838315542A external-priority patent/GB8315542D0/en
Priority claimed from GB838327859A external-priority patent/GB8327859D0/en
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Assigned to FUJISAWA PHARMACEUTICAL CO., LTD. reassignment FUJISAWA PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ITO, KIYOTAKA, MURATA, MASAYOSHI, TAKAYA, TAKAO
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to new pyrimidine derivatives. More particularly, this invention relates to new pyrimidine derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities, processes for preparation thereof, a pharmaceutical composition comprising the same and method of use thereof.
  • one object of this invention is to provide the new and useful pyrimidine derivatives and pharmaceutically acceptable salt thereof.
  • Another object of this invention is to provide processes for preparation of the pyrimidine derivatives and pharmaceutically acceptable salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising said pyrimidine derivative or pharmaceutically acceptable salt thereof as a cardiotonic, antihypertensive agent, cerebrovascular vasodilator and anti-platelet agent.
  • Still further object of this invention is to provide a method of using said pyrimidine derivative or a pharmaceutically acceptable salt thereof for therapeutic treatment of heart disease, hypertension, cerebrovascular disease and thrombosis of human being and animals.
  • pyrimidine derivatives of this invention are novel and represented by the following general formula [I]: ##STR3## wherein Z is a group selected from ##STR4## in which R 1 and R 2 are each hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino and R 5 is lower alkyl,
  • R 3 is hydrogen, aryl optionally substituted with lower alkyl, lower alkoxy and/or halogen, or pyridyl optionally substituted with lower alkyl,
  • R 4 is hydrogen, lower alkyl or phenyl optionally substituted with lower alkoxy
  • Y is ⁇ O, ⁇ S or ⁇ N--R 6 , in which R 6 is lower alkyl; cyclo(lower)alkyl; ar(lower)alkyl optionally substituted with lower alkoxy; N-containing unsaturated heterocyclic group optionally substituted with lower alkyl; or aryl optionally substituted with hydroxy, lower alkyl, halogen and/or lower alkoxy, in which lower alkoxy substituent may be substituted with epoxy, hydroxy, amino and/or lower alkylamino,
  • Y is ⁇ N--R 6 when R 3 and R 4 are each hydrogen, and Y is ⁇ S or ⁇ N--R 6 when R 1 and R 2 are each hydrogen or lower alkyl and R 3 is phenyl.
  • the object compound [I] the following points are to be noted. That is, when Z is a group of the formula: ##STR5## R 1 and/or R 2 are hydrogen, then the pyrimidine moiety in the object compound [I] can be alternatively represented by its tautomers. For example, when both of R 1 and R 2 are hydrogen and Y is ⁇ N--R 6 , the compound [I] can be represented by one of the structural formula (A) to (E) as shown in the following. ##STR6## wherein R 3 , R 4 and R 6 are each as defined above.
  • the object compound may be presented in any of these tautomeric forms and may co-exist in an equilibrium mixture. Accordingly all of these tautomeric forms are included within the scope of the present invention.
  • the pyrimidine moiety in the object compound [I] also includes its tautomeric isomers, and can be represented by substantially the same tautomerism as illustrated above.
  • the object compound [I] and their salts of the present invention can be prepared by the following processes. ##STR7## wherein R 1 , R 2 , R 3 , R 4 , R 6 and Z are each as defined above,
  • R a 1 and R a 2 are hydrogen and another is hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino,
  • R b 1 and R b 2 is alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino and another is hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino,
  • R c 1 and R c 2 are lower alkyl which is substituted with epoxy and another is hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino,
  • R d 1 and R d 2 are lower alkyl which is substituted with hydroxy and amino or lower alkylamino and another is hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with hydroxy, amino and/or lower alkylamino,
  • R 7 is alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino,
  • R 8 is lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino
  • R a 8 is lower alkyl substituted with epoxy
  • R b 8 is lower alkyl substituted with hydroxy and amino or lower alkylamino
  • X is a leaving group
  • Y a is ⁇ O or ⁇ N--R 6 , in which
  • R 6 is as defined above, and
  • Z a is a group of the formula: ##STR8## in which R 1 , R 2 and R 5 are each as defined above, provided that Y is ⁇ N--R 6 when R 3 and R 4 are each hydrogen, and Y is ⁇ S or ⁇ N--R 6 when R 1 and R 2 are each hydrogen or lower alkyl and R 3 is phenyl.
  • R a 1 , R b 1 , R c 1 and R d 1 are included in the scope of the definition of R 1
  • R a 2 , R b 2 , R c 2 and R d 2 are included in the scope of the definition of R 2
  • R a 8 and R b 8 are also included in the scope of the definition of R 8 .
  • the suitable examples and illustrations for R a 1 to R d 1 , R a 2 to R d 2 and R a 8 to R b 8 are to be referred to those for R 1 , R 2 and R 8 , respectively.
  • Suitable examples of lower alkyl for R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like.
  • the lower alkyl group for R 1 , R 2 , R 7 and R 8 may be substituted with epoxy, hydroxy, amino, and/or lower alkylamino [e.g. methylamino, ethylamino, propylamino, butylamino, t-butylamino, pentylamino, hexylamino, etc.].
  • lower alkylamino e.g. methylamino, ethylamino, propylamino, butylamino, t-butylamino, pentylamino, hexylamino, etc.
  • Suitable examples of the lower alkyl group having such substitutent(s) may be epoxy substituted lower alkyl [e.g. 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5-epoxypentyl, 4,6-epoxyhexyl, etc.], hydroxy substituted lower alkyl [e.g. hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 6-hydroxyhexyl, etc.], amino substituted lower alkyl [e.g.
  • methylaminomethyl dimethylaminomethyl, 2-(methylamino)ethyl, 2-(diethylamino)ethyl, 2-(methylamino)propyl, 3-(ethylamino)propyl, 3-(isopropylamino)propyl, 3-(t-butylamino)propyl, 6-(hexylamino)hexyl, etc.], hydroxy and lower alkylamino substituted lower alkyl [e.g.
  • Suitable examples of alkenyl for R 1 , R 2 and R 7 may be vinyl, allyl, propenyl, isopropenyl, butenyl, pentenyl or the like.
  • Suitable examples of ar(lower)alkyl for R 1 , R 2 and R 7 may be benzyl, phenethyl, 3-phenylpropyl, benzhydryl, trityl or the like.
  • Suitable examples of aryl for R 3 and R 6 may include phenyl, naphthyl and the like.
  • the aryl group for R 3 may be optionally substituted with lower alkoxy [e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc.], halogen [e.g. chlorine, bromine, fluorine, iodine] and/or the aforementioned lower alkyl.
  • lower alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc.
  • halogen e.g. chlorine, bromine, fluorine, iodine
  • Suitable examples of the aryl group for R 3 having such substituent(s) may be lower alkoxy substituted phenyl [e.g. 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2-ethoxyphenyl, 4-hexyloxyphenyl, etc.], halogenated phenyl [e.g.
  • the pyridyl group for R 3 may include pyridyl [e.g. 2-pyridyl, 3-pyridyl and 4-pyridyl] and pyridinio, and these pyridyl groups may be optionally substituted with the aforementioned lower alkyl.
  • Suitable examples of the pyridyl group for R 3 having such substituent(s) may be 2-methylpyridyl, 3-ethylpyridyl, 3-ethyl-6-methylpyridyl, 1-methylpyridinio, 1-ethylpyridinio, 1-hexylpyridinio or the like.
  • the phenyl group for R 4 may be optionally substituted with lower alkoxy group, suitable examples of which can be referred to those as exemplified for the lower alkoxy substituted phenyl for R 3 .
  • Suitable examples of cyclo(lower)alkyl for R 6 may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.
  • the aryl group for R 6 may be optionally substituted with hydroxy, lower alkyl, halogen and/or lower alkoxy, in which lower alkoxy substituent may be substituted with epoxy, hydroxy, amino and/or lower alkylamino.
  • Suitable examples of the aryl group for R 6 having such substituent(s) may be lower alkyl substituted phenyl, halogenated phenyl, lower alkyl and halogen substituted phenyl, lower alkoxy substituted phenyl as exemplified before for R 3 , respectively, or hydroxy substituted phenyl [e.g. 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, etc.].
  • the lower alkoxy moiety of said lower alkoxy substituted phenyl group may be further substituted with epoxy, hydroxy, amino and/or lower alkylamino.
  • Suitable examples of the lower alkoxy substituted phenyl having these additional substituent(s) may be 4-(2,3-epoxypropoxy)phenyl, 2-(hydroxymethoxy)phenyl, 4-(2-aminoethoxy)phenyl, 4-(3-methylaminopropoxy)phenyl, 4-(2-hydroxy-3-isopropylaminopropoxy)phenyl, 4-(3-t-butylamino-2-hydroxypropoxy)phenyl or the like.
  • Suitable examples of ar(lower)alkyl for R 6 may be benzyl, phenethyl, 3-phenylpropyl, benzhydryl, trityl or the like.
  • Said ar(lower)alkyl groups may be optionally substituted with the aforementioned lower alkoxy, and suitable examples of the ar(lower)alkyl group having such substituent(s) may be lower alkoxy substituted benzyl [e.g. 4-methoxybenzyl, 2-ethoxybenzyl, 3,4-dimethoxybenzyl, etc.], lower alkoxy substituted benzhydryl [e.g. 4-methoxybenzhydryl, 4,4'-dimethoxybenzhydryl, etc.] or the like.
  • N-containing unsaturated heterocyclic group for R 6 may be 5- or 6-membered N-containing unsaturated heterocyclic group such as pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, thiadiazolyl, [e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, etc.] or the like.
  • These N-containing unsaturated heterocyclic groups may be substituted with lower alkyl as exemplified before.
  • Suitable examples of the N-containing unsaturated heterocyclic group having such substituent(s) may be 4-methylpyridyl, 2,4,6-trimethylpyridyl, 5-methyl-1,3,4-thiadiazolyl or the like.
  • Suitable examples of the leaving group for X may be halide [e.g. chloride, bromide, iodide, etc.], sulfonate [e.g. methanesulfonate, benzenesulfonate, toluenesulfonate, etc.] or the like.
  • halide e.g. chloride, bromide, iodide, etc.
  • sulfonate e.g. methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts and include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.], an organic acid salt [e.g.
  • a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzy
  • formate acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.] an inorganic acid salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arginine salt, ornithine salt, etc.], and the like.
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. arginine salt, ornithine salt, etc.
  • the object compound [Ia] and its salt can be prepared by reacting a compound [II] or its reactive derivative at the carboxy group or a salt thereof with a compound [III] or its salt.
  • Suitable salts of the compounds [II] and [III] may be the same as those exemplified for the compound [I].
  • Suitable reactive derivative at the carboxy group of the compound [II] may include an ester, an acid halide, an acid anhydride and the like.
  • the suitable examples of the reactive derivatives may be an acid halide [e.g. acid chloride, acid bromide, etc.]; a symmetrical acid anhydride; a mixed acid anhydride with an acid such as aliphatic carboxylic acid [e.g. acetic acid, pivalic acid, etc.], substituted phosphoric acid [e.g. dialkylphosphoric acid, diphenylphosphoric acid, etc.]; an ester such as lower alkyl ester [e.g.
  • phenyl ester tolyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphthyl ester, etc.], or an ester with N,N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxy-6-chloro-1H-benzotriazole, or the like.
  • These reactive derivatives can be optionally selected according to the kind of the compound [II] to be used.
  • This reaction is usually carried out in a conventional solvent such as water, methanol, ethanol, propanol, tetralin, tetrahydrofuran, dioxane, chloroform, toluene, dimethylformamide, dimethylsulfoxide or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, methanol, ethanol, propanol, tetralin, tetrahydrofuran, dioxane, chloroform, toluene, dimethylformamide, dimethylsulfoxide or any other organic solvent which does not adversely influence the reaction.
  • This reaction is preferably conducted in the presence of an acid such as inorganic acid [e.g. hydrochloric acid, sulfuric acid, polyphosphoric acid, etc.], organic acid [e.g. trifluoroacetic acid, benzenesulfonic acid, toluenesulfonic acid, etc.] or the like.
  • an acid such as inorganic acid [e.g. hydrochloric acid, sulfuric acid, polyphosphoric acid, etc.], organic acid [e.g. trifluoroacetic acid, benzenesulfonic acid, toluenesulfonic acid, etc.] or the like.
  • the reaction can also be conducted under dehydrating condition such as an azeotropic dehydration, in the presence of a dehydrating agent [e.g. magnesium sulfate, anhydrous zinc chloride, phosphorus pentoxide, zeolite, silica gel, etc.] or the like.
  • a dehydrating agent e.g. magnesium sulfate, anhydrous zinc chloride, phosphorus pentoxide, zeolite, silica gel, etc.
  • the reaction is preferably carried out in the presence of a conventional condensing agent.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound [Ic] and its salt can be prepared by reacting a compound [Ib] or its salt with a compound [IV] or its salt.
  • Suitable salts of the compound [IV] may be the same as those exemplified for the compound [I].
  • This reaction is preferably conducted in the presence of a base such as alkali metal hydride [e.g. sodium hydride, potassium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, magnesium hydride, etc.], alkali metal hydroxide [e.g. sodium hydroxide, potassium hydroxide, etc.], alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], alkali metal alkoxide [e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.] or the like.
  • a base such as alkali metal hydride [e.g. sodium hydride, potassium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, magnesium hydride, etc.], alkali metal hydroxide [e.g. sodium hydroxide
  • This reaction is usually carried out in a conventional solvent such as water, methanol, ethanol, propanol, tetrahydrofuran, dioxane, acetonitrile, methylene chloride, chloroform, benzene, dimethylformamide, dimethyl sulfoxide or any other organic solvent which does not adversely influence the reaction.
  • solvent can be optionally selected according to the kinds of the starting compound [Ib], the base and the compound [IV], especially to the kind of the base to be used.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound [Id] and its salt can be prepared by alkylating a compound [Ib] or its salt.
  • reaction is carried out in substantially the same manner as that of Process 2, and therefore the reaction mode and reaction conditions [e.g. base, solvent, reaction temperature, etc.] of this process are to be referred to those as explained in Process 2.
  • reaction mode and reaction conditions e.g. base, solvent, reaction temperature, etc.
  • the object compound [If] and its salt can be prepared by reacting a compound [Ie] or its salt with ammonia or lower alkyl amine or a salt thereof.
  • Suitable salts of ammonia and the lower alkyl amine may be acid addition salts as exemplified for the compound [I].
  • Suitable examples of the lower alkyl amine to be used in this reaction may include primary and secondary amine such as methylamine, ethylamine, propylamine, butylamine, t-butylamine, pentylamine, hexylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, dihexylamine and the like.
  • This reaction is usually carried out in a conventional solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane, methylene chloride, chloroform, benzene, dimethylformamide, dimethyl sulfoxide or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane, methylene chloride, chloroform, benzene, dimethylformamide, dimethyl sulfoxide or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound [Ih] and its salt can be prepared by reacting a compound [Ig] or its salt with phosphorus pentasulfide.
  • This reaction is usually carried out in a conventional solvent such as benzene, toluene, xylene, pyridine, tetrahydrofuran, dioxane or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as benzene, toluene, xylene, pyridine, tetrahydrofuran, dioxane or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical, and the reaction is usually carried out under warming or heating.
  • the object compound [Ii] and its salt can be prepared by reacting a compound [Ih] or its reactive derivative at the thioxo group or a salt thereof with a compound [V] or its salt.
  • Suitable salts of the compound [V] may be the same as those exemplified for the compound [I].
  • This reaction is usually carried out in a conventional solvent such as methanol, ethanol, propanol, tetrahydrofuran, dioxane, methylene chloride, dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as methanol, ethanol, propanol, tetrahydrofuran, dioxane, methylene chloride, dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • the compound [V] is liquid, it can also be used as a solvent.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • Suitable reactive derivative at the thioxo group of the compound [Ih] may be S-alkyl derivative [e.g. S-methyl derivative, S-ethyl derivative, S-octyl derivative, etc.], S-ar(lower)alkyl derivative [e.g. S-benzyl derivative, etc.] or the like.
  • These reactive derivatives can be prepared by reacting a compound [Ih] or its salt with an alkylating agent such as alkyl halide [e.g. methyl iodide, ethyl iodide, octyl bromide, etc.], ar(lower)alkyl halide [e.g.
  • the object compound [Ik] and its salt can be prepared by reacting a compound [Ij] or its salt with a compound [VI] or its salt.
  • Suitable salts of the compound [VI] may be acid addition salts as exemplified for the compound [I].
  • reaction is carried out in substantially the same manner as that of Process 2, and therefore the reaction mode and reaction conditions [e.g. base, solvent, reaction temperature, etc.] of this process are to be referred to those as explained in Process 2.
  • reaction mode and reaction conditions e.g. base, solvent, reaction temperature, etc.
  • the object compound [Im] and its salt can be prepared by aminating a compound [Il] or its salt.
  • reaction is carried out in substantially the same manner as that of Process 4, and therefore the reaction mode and reaction conditions [e.g. aminating agent, solvent, reaction temperature, etc.] of this process are to be referred to those as explained in Process 4.
  • reaction mode and reaction conditions e.g. aminating agent, solvent, reaction temperature, etc.
  • each of the object compound [I] and the starting compounds [II], [III], [IV], [V] and [VI] include one or more stereoisomers due to asymmetric carbon atoms in the molecule, and all of such isomers of the compounds [I]; [II], [III], [IV], [V] and [VI] are included within the scope of this invention.
  • the new pyrimidine derivatives [I] and pharmaceutical acceptable salts thereof possess a cardiotonic activity, anti-platelet activity, cerebrovascular vasodilative activity and antihypertensive activity, and are useful for a therapeutic treatment of heart disease [e.g. cardiac insufficiency, etc.], thombosis, cerebrovascular disease and hypertension.
  • cardiotonic test data For the purpose of showing pharmaceutical activity of the pyrimidine derivatives [I], cardiotonic test data, inhibitory activity test data on platelet aggregation, cerebrovascular vasodilative test data and antihypertensive test data are illustrated in the following.
  • Another catheter was positioned in the vena cave through right femoral vein for injection of drugs.
  • Systemic blood pressure, left ventricular pressure, dp/dt max and heart rate were recorded simultaneously on a polygram (Nihonkohden, RJG-4008).
  • Test compound was dissolved in distilled water (0.2 ml/kg) or dimethyl sulfoxide (0.04 ml/kg) and injected into the femoral vein. The parameters after dosing were compared with those during the predosing period.
  • Test results were represented in terms of percentage of dp/dt max changes (dp/dt M.C) calculated by following formula, and are shown in table 1. ##EQU1## Test Results A
  • Test Method B Anti-platelet activity:
  • Platelet rich plasma which contains 6.5-7.5 ⁇ 10 8 platelet/ml was prepared from rabbit blood.
  • PRP Platelet rich plasma
  • 5 ⁇ l of calcium chloride (1 mM) and 50 ⁇ l of pH 7.4 Tris-acetate solution (5 mM) containing 120 mM NaCl and test compound were added successively, and then stirred for 2 min. at 37° C.
  • 5 ⁇ l of adenosine diphosphate (ADP) (2.5 ⁇ M) or collagen (2.5 ⁇ g/ml) was added as an aggregation inducer. Aggregation was measured by using an aggregometer (NKK HEMA TRACER 1). ID 50 is shown in Table 2.
  • Mongrel dogs of either sex were anesthetized with sodium pentobarbital (35 mg/kg. i.p.). After the external carotid artery was ligated, a flowmeter probe was fitted to the common carotid artery. Polyethylene cannulas were inserted in the femoral artery for measurement of blood pressure and in the saphenous vein for injection of drug. Blood pressure was measured with a pressure transducer and the arterial pulse was also used to trigger a heart rate meter. Blood pressure, heart rate and cerebral blood flow (C.B.F.) were recorded on a polygraph.
  • C.B.F. cerebral blood flow
  • Test compound was dissolved in an equimolar solution of hydrochloric acid and diluted with water (0.2 ml/kg), and injected intravenously. The prarmeters after dosing were compared with those during the predosing period.
  • test compounds were administered orally. Blood pressure was measured at the femoral artery by means of a pressure transducer and recorded as electrically integrated values of mean arterial pressure.
  • the object compound [I] of the present invention are useful as cardiotonics, antihypertensive agents, cerebrovascular vasodilators and anti-platelet agents.
  • the object compounds [I] of the present invention and pharmaceutically acceptable salts thereof are used in a form of the conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral of external administration.
  • a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral of external administration.
  • the pharmaceutical preparation may be compounded in a solid form such as capsule, tablet, dragee or suppository, or in a liquid form such as solution, suspension or emulsion. If needed, there may be included in the above preparation auxiliary substance, stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
  • the effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 500 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.
  • 1,3-Dimethyl-6-(4-methoxy-2-methylphenyl)-2,4(1H,3H)pyrimidinedione (4.8 g) was obtained according to substantially the same manner as that of Example 2 from ethyl 2-(4-methoxy-3-methylbenzyl)acetate (5.0 g) and N,N'-dimethylurea (2.05 g).
  • 6-(3,4-Dichlorophenyl)-1,3-dimethyl-2,4(1H,3H)pyrimidinedione (5.27 g) was obtained according to substantially the same manner as that of Example 2 from ethyl 2-(3,4-dichlorobenzoyl)acetate (10.0 g) and N,N'-dimethylurea (3.71 g).
  • 1,3-Dimethyl-6-(2,3,4-trimethoxyphenyl)-2,4(1H,3H)pyrimidinedione (5.58 g) was obtained according to substantially the same manner as that of Example 2 from ethyl 2-(2,3,4-trimethoxybenzoyl)acetate (10.0 g) and N,N'-dimethylurea (3.75 g).
  • 6-(4-Methoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (18.7 g) was obtained according to substantially the same manner as that of Example 8 from ethyl 2-(4-methoxybenzoyl)acetate (100 g) and N-methylurea (33.3 g).
  • 1,3-Dimethyl-6-(3,4,5-trimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (2.1 g) was obtained according to the substantially same manner as that of Example 10 from ethyl 2-(3,4,5-trimethoxybenzoyl)acetate (2.82 g) and N,N'-dimethylurea (0.97 g).
  • 6-(3,4-Dimethoxyphenyl)-1-(2,3-epoxypropyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (4.02 g) was obtained according to substantially the same manner as that of Example 17 from 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (6.9 g), sodium hydride (60% in oil, 1.16 g) and epichlorohydrin (30 ml).
  • 1,3-Dimethyl-6-(4-methoxyphenyl)-2,4(1H,3H)-pyrimidinedione (3.1 g) was obtained according to substantially the same manner as that of Example 17 from 6-(4-methoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (5.0 g), sodium hydride (50% in oil, 1.1 g) and methyl iodide (6.7 ml).
  • 3,4-Dihydro-1,3-dimethyl-6-phenyl-4-thioxo-2(1H)-pyrimidinone (3.0 g) was obtained according to the substantially same manner as that of Example 29 from 1,3-dimethyl-6-phenyl-2,4(1H,3H)-pyrimidinedione (4.0 g) and phosphorus pentasulfide (4.7 g).
  • 3,4-Dihydro-1,3-dimethyl-6-(3-pyridyl)-4-thioxo-2(1H)-pyrimidinone (0.69 g) was obtained according to the substantially same manner as that of Example 29 from 1,3-dimethyl-6-(3-Pyridyl)-2,4(1H,3H)-pyrimidinedione (0.78 g) and phosphorus pentasulfide (0.92 g).
  • 3,4-Dihydro-1,3-dimethyl-6-(4-methoxy-2-methylphenyl)-4-thioxo-2(1H)-pyrimidinone (3.51 g) was obtained according to substantially the same manner as that of Example 29 from 1,3-dimethyl-6-(4-methoxy-2-methylphenyl)-2,4(1H,3H)pyrimidinedione (4.80 g) and phosphorus pentasulfide (8.17 g).
  • 3,4-Dihydro-1,3-dimethyl-6-(4-methoxyphenyl)-4-thioxo-2(1H)-pyrimidinone (2.4 g) was obtained according to substantially the same manner as that of Example 29 from 1,3-dimethyl-6-(4-methoxyphenyl)-2,4(1H,3H)-pyrimidinedione (3.0 g) and phosphorus pentasulfide (8.1 g).
  • 3,4-Dihydro-6-(3,4-dimethoxyphenyl)-4-thioxo-2(1H)-pyrimidinone (0.63 g) was obtained according to substantially the same manner as that of Example 29 from 6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (1.09 g) and phosphorus pentasulfide (1.00 g).
  • 1,3-Diethyl-3,4-dihydro-6-(3,4-dimethoxyphenyl)-4-thioxo-2(1H)-pyrimidinone (1.74 g) was obtained according to the substantially same manner as that of Example 43 from 1,3-diethyl-6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (2.0 g) and phosphorus pentasulfide (4.0 g).
  • 3,4-Dihydro-1,3-dimethyl-6-phenyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.81 g) was obtained according to the substantially same manner as that of Example 48 from 3,4-dihydro-1,3-dimethyl-6-phenyl-4-thioxo-2(1H)-pyrimidinone (1.0 g), methyl iodide (22.7 ml) and 2,4,6-trimethylaniline (3.6 g).
  • 3,4-Dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-phenylimino-2(1H)-pyrimidinone (0.64 g) was obtained according to substantially the same manner as that of Example 48 from 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.0 g), methyl iodide (20 ml) and aniline (3.0 g).
  • 3,4-Dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(2,6-dimethylphenylimino)-2(1H)-pyrimidinone (0.75 g) was obtained according to substantially the same manner as that of Example 48 from 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.0 g), methyl iodide (20 ml) and 2,6-dimethylaniline (2.0 g).
  • 1,3-Diethyl-3,4-dihydro-6-(3,4-dimethoxyphenyl)-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.69 g) was obtained according to the substantially same manner as that of Example 72 from 1,3-diethyl-3,4-dihydro-6-(3,4-dimethoxyphenyl)-4-thioxo-2(1H)-pyrimidinone (1.0 g) methyl iodide (40 ml) and 2,4,6-trimethylaniline (3.0 g), except that toluene was used as solvent in the place of tetrahydrofuran.
  • 3,4-Dihydro-6-(3,4-dimethoxyphenyl)-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.62 g) was obtained according to substnatially the same manner as that of Example 48 from 3,4-dihydro-6-(3,4-dimethoxyphenyl)-4-thioxo-2(1H)-pyrimidinone (0.6 g), methyl iodide (3 ml) and 2,4,6-trimethylaniline (3 ml).

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US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11674163B2 (en) 2010-01-27 2023-06-13 Arena Pharmaceuticals, Inc. Processes for the preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US12156866B2 (en) 2018-06-06 2024-12-03 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4746664A (en) * 1983-03-25 1988-05-24 Fujisawa Pharmaceutical Co., Ltd. Substituted-3,4-dihydro-4-(2,4,6-trimethoxyphenylimino)-2(1H)-pyrimidones useful as cardiotonic, antihypertensive, cerebrovascular vasodilator and anti-platelet agent
US4824851A (en) * 1983-03-25 1989-04-25 Fujisawa Pharmaceutical Co., Ltd. Pyrimidones as cardiotonic, anti hypertensive, cerebrovascular vasodilator and anti-platelet agents
US11674163B2 (en) 2010-01-27 2023-06-13 Arena Pharmaceuticals, Inc. Processes for the preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11896578B2 (en) 2015-01-06 2024-02-13 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US12156866B2 (en) 2018-06-06 2024-12-03 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor

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